**3.2 Cardiovascular autonomic neuropathy**

CAN defined as the "impairment of autonomic control of the cardiovascular system in the setting of diabetes after exclusion of other causes" [23]. The prevalence of CAN varies from 31–73% in T2DM patients [17]. The T2DM patients with a higher age, longer duration of diabetes, poor and perhaps unstable glycaemic control, comorbid diabetic polyneuropathy, retinopathy and nephropathy, hypertension (on treatment), and other cardiovascular risk factors (in particular obesity and metabolic dyslipidaemia) are high risk of developing CAN [24].

CAN results from impairment of autonomic regulation on heart and blood vessels with consequent alteration of cardiovascular hemodynamic functions [20]. Underlying pathogenesis of CAN first damages longest autonomic nerve. Thus, CAN initially (subclinical CAN) begins with reduced parasympathetic control, as vagus is the longest autonomic nerve, with the consequent sympathovagal imbalance. Hence, reduced HRV is the earliest marker of CAN [20]. Subclinical CAN be even seen in prediabetes [24]. As subclinical CAN progresses

#### **Figure 1.**

*Summary of the mechanisms that relate hyperglycemia to microvascular complications in patients with diabetes [9, 15, 18, 20, 21]. PKC: Protein kinase C; AGE: Advanced glycation end-products; GAPDH: Glyceraldehyde-3 phosphate dehydrogenase; GSH: Glutathione; NADH: Nicotinamide adenine dinucleotide; TGF-*β*: Transforming growth factor; VEGF: Vascular endothelial growth factor; PAI-1: Plasminogen activator inhibitor-1; eNOS: Endothelial nitric oxide.*

**299**

*Type 2 Diabetes Mellitus: Cardiovascular Autonomic Neuropathy and Heart Rate Variability*

into clinical CAN, sympathetic tone augments during early stage and followed by sympathetic denervation in later stage (**Figure 2**). This denervation begins at the apex of the heart and advances towards the base of the heart. This disproportionate sympathetic denervation of ventricles predisposes to the development of cardiac arrhythmias. CAN is also associated with silent myocardial infarction (MI) and sudden death. CAN is highly associated with cardiovascular morbidity and mortality and thus, it is crucial to be diagnosed at its early stage to prevent

Clinical CAN is usually diagnosed and its severity is assessed by autonomic score obtained through five standard cardiovascular autonomic reflex tests (CARTs): (1) the HR response to deep breathing (2) the HR response to standing (3) the Valsalva maneuver (4) the blood pressure response to standing and (5) the blood pressure response to sustained handgrip [26]. Whereas, subclinical CAN is diagnosed based on changes in HRV, baroreflex sensitivity, and cardiac imaging showing increased torsion of the left ventricle [26]. Sensitivity of standards CARTs to detect subclinical CAN is very limited as no significant changes are seen on standard CARTs [26]. Detecting CAN at subclinical stage is of paramount importance to provide early intervention on modifiable risk factors of CAN to prevent progres-

Heart rate is controlled by changes in sympathetic and parasympathetic influences, neurohumoral factors (epinephrine and thyroid hormones), ionic concentrations (calcium and potassium) and local temperature of SA node [27]. But, the HRV measured over short period of time (5 minutes) at rest is largely determined by changes of autonomic nervous system control (predominantly by the vagal tone) and the stretch of SA node [22]. On the contrary, long-term measurement of HRV obtained through 24-hour Holter ECG can be influenced by concomitant illness, use of medications, and lifestyle factors (exercise, stress, smoking, etc.) in addition to afore mentioned factors [22]. HRV is also varies due to other physiological factors (**Table 1**). Short-term HRV (5 minutes) measurement is a reliable technique to detect autonomic dysfunction [9]. HRV describes the variations of both instantaneous heart rate and RR intervals which in turn reflect the cardiac autonomic nervous control (**Figure 3**) [13]. HRV measurement obtained from 5 min-ECG recording represents marker for the measurement of resting autonomic tonic activity; the balance between sympathetic & parasympathetic nervous activity at any instant. Thus, alteration of HRV can detect the impairment of resting sympathetic and parasympathetic activity individually and shift of the normal sympathovagal

*DOI: http://dx.doi.org/10.5772/intechopen.95515*

*Progression of CAN with signs and symptoms [9, 22].*

these complications [25].

**Figure 2.**

**4. Heart rate variability**

sion CAN to its severe or advanced form [24, 26].

*Type 2 Diabetes Mellitus: Cardiovascular Autonomic Neuropathy and Heart Rate Variability DOI: http://dx.doi.org/10.5772/intechopen.95515*

#### **Figure 2.**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

**3.2 Cardiovascular autonomic neuropathy**

endothelial damage, vasoconstriction, neuronal hypoxia, neuronal cell necrosis,

CAN defined as the "impairment of autonomic control of the cardiovascular system in the setting of diabetes after exclusion of other causes" [23]. The prevalence of CAN varies from 31–73% in T2DM patients [17]. The T2DM patients with a higher age, longer duration of diabetes, poor and perhaps unstable glycaemic control, comorbid diabetic polyneuropathy, retinopathy and nephropathy, hypertension (on treatment), and other cardiovascular risk factors (in particular obesity

CAN results from impairment of autonomic regulation on heart and blood vessels with consequent alteration of cardiovascular hemodynamic functions [20]. Underlying pathogenesis of CAN first damages longest autonomic nerve. Thus, CAN initially (subclinical CAN) begins with reduced parasympathetic control, as vagus is the longest autonomic nerve, with the consequent sympathovagal imbalance. Hence, reduced HRV is the earliest marker of CAN [20]. Subclinical CAN be even seen in prediabetes [24]. As subclinical CAN progresses

*Summary of the mechanisms that relate hyperglycemia to microvascular complications in patients with diabetes [9, 15, 18, 20, 21]. PKC: Protein kinase C; AGE: Advanced glycation end-products; GAPDH: Glyceraldehyde-3 phosphate dehydrogenase; GSH: Glutathione; NADH: Nicotinamide adenine dinucleotide; TGF-*β*: Transforming growth factor; VEGF: Vascular endothelial growth factor; PAI-1: Plasminogen activator* 

neuronal apoptosis and axonal degeneration (**Figure 1**) [9, 16, 19, 21, 22].

and metabolic dyslipidaemia) are high risk of developing CAN [24].

**298**

**Figure 1.**

*inhibitor-1; eNOS: Endothelial nitric oxide.*

*Progression of CAN with signs and symptoms [9, 22].*

into clinical CAN, sympathetic tone augments during early stage and followed by sympathetic denervation in later stage (**Figure 2**). This denervation begins at the apex of the heart and advances towards the base of the heart. This disproportionate sympathetic denervation of ventricles predisposes to the development of cardiac arrhythmias. CAN is also associated with silent myocardial infarction (MI) and sudden death. CAN is highly associated with cardiovascular morbidity and mortality and thus, it is crucial to be diagnosed at its early stage to prevent these complications [25].

Clinical CAN is usually diagnosed and its severity is assessed by autonomic score obtained through five standard cardiovascular autonomic reflex tests (CARTs): (1) the HR response to deep breathing (2) the HR response to standing (3) the Valsalva maneuver (4) the blood pressure response to standing and (5) the blood pressure response to sustained handgrip [26]. Whereas, subclinical CAN is diagnosed based on changes in HRV, baroreflex sensitivity, and cardiac imaging showing increased torsion of the left ventricle [26]. Sensitivity of standards CARTs to detect subclinical CAN is very limited as no significant changes are seen on standard CARTs [26]. Detecting CAN at subclinical stage is of paramount importance to provide early intervention on modifiable risk factors of CAN to prevent progression CAN to its severe or advanced form [24, 26].

#### **4. Heart rate variability**

Heart rate is controlled by changes in sympathetic and parasympathetic influences, neurohumoral factors (epinephrine and thyroid hormones), ionic concentrations (calcium and potassium) and local temperature of SA node [27]. But, the HRV measured over short period of time (5 minutes) at rest is largely determined by changes of autonomic nervous system control (predominantly by the vagal tone) and the stretch of SA node [22]. On the contrary, long-term measurement of HRV obtained through 24-hour Holter ECG can be influenced by concomitant illness, use of medications, and lifestyle factors (exercise, stress, smoking, etc.) in addition to afore mentioned factors [22]. HRV is also varies due to other physiological factors (**Table 1**). Short-term HRV (5 minutes) measurement is a reliable technique to detect autonomic dysfunction [9]. HRV describes the variations of both instantaneous heart rate and RR intervals which in turn reflect the cardiac autonomic nervous control (**Figure 3**) [13]. HRV measurement obtained from 5 min-ECG recording represents marker for the measurement of resting autonomic tonic activity; the balance between sympathetic & parasympathetic nervous activity at any instant. Thus, alteration of HRV can detect the impairment of resting sympathetic and parasympathetic activity individually and shift of the normal sympathovagal


**Table 1.**

*Physiological factors to be considered while measuring HRV.*

#### **Figure 3.**

*Heart rate variability (HRV). Ms: Milliseconds, bpm: Beats per minute, R-R int.: R-R interval.*

#### **Figure 4.**

*Quantification of HRV into time domain and frequency parameters along with Poincare plot.*

balance. HRV is quantified or measured by three methods; time domain, frequency domain and nonlinear analysis of short-term (5 mins) and long-term ECG (24 hrs.) recording (**Figure 4**). HRV test is an accurate quantitative and reproducible measurement of autonomic nerve function [13].

#### **4.1 Time and frequency domain, and non-linear analysis of HRV**

The time domain method measures the heart rate at any point either in time or in the intervals between successive QRS complex of a continuous ECG record. The interval between adjacent QRS complexes is known as normal-to normal (NN) interval. HRV time-domain indices quantify the amount of HRV observed during monitoring periods that may range from <1 min to >24 h. Time domain variables include the SDNN, SDANN, SDNNI, RMSSD, NN50, pNN50, HR Max − HR Min (**Table 2**) [28] (**Figure 5**).

Frequency domains variables (**Table 3**) are derived through many methods. Fast Fourier Transformation (FFT) is one the commonest methods to derive frequency components of HRV. Power spectrum derived through FFT is subsequently categorized into different bands of frequencies: VLF- (0.0033 to 0.04) Hz, LF- (0.04 to 0.15) Hz and HF- (0.15 to 0.4) Hz. Power spectral densities (PSD) are then plotted

**301**

in ms2

**Figure 5.**

ms2

*Type 2 Diabetes Mellitus: Cardiovascular Autonomic Neuropathy and Heart Rate Variability*

**Variable Unit Description Physiological** 

SDNN\* Ms Standard deviation of NN intervals Reflects PNS

each 5 min segment of a 24 h HRV recording

Ms Mean of the standard deviations of all the NN intervals for each 5 min segment of a 24 h HRV recording

of differences between adjacent RR intervals.

Bpm The average difference between the highest and lowest HRs during each respiratory cycle

**"***Reflects PNS function. RSA: respiratory sinus arrhythmia. Bpm: beats per minute. PNS: parasympathetic nervous* 

NN50 Ms Number of R-R interval differences ≥50 ms "

*\*It is more accurate when measured from 24 h-ECG recording than that measured from shorter period.*

SDANN ms Standard deviation of the average NN intervals for

pNN50 % Percentage of successive RR intervals that differ by more than 50 ms

*Time domain variables of HRV with physiological significance.*

RMSSD Ms The Root square of the mean of the sum of the squares

**correlates**

function

"

"

"

"

Mediated by RSA

/Hz against preset frequencies. Power of the spectral bands are calculated in

*Time domain, frequency domain measurements and Poincare plot of HRV obtained through RMS Polyrite.*

 (absolute power) and in normalized units (n.u). For example, normalize unit of LF is calculated by the formula: [LF/total power-VLF] × 100. Power of LF and HF are established in short term analysis of HRV. Nonlinear method of HRV analysis (**Table 4**) through Poincare plot is done by plotting every RR interval against the

prior interval consequently forming a scatter plot.

*DOI: http://dx.doi.org/10.5772/intechopen.95515*

SDNN index

Max HR-Min HR

*system.*

**Table 2.**

*Type 2 Diabetes Mellitus: Cardiovascular Autonomic Neuropathy and Heart Rate Variability DOI: http://dx.doi.org/10.5772/intechopen.95515*


*\*It is more accurate when measured from 24 h-ECG recording than that measured from shorter period.* **"***Reflects PNS function. RSA: respiratory sinus arrhythmia. Bpm: beats per minute. PNS: parasympathetic nervous system.*
